Recent developments in photonic technology provide the ability to non-invasively image in vivo; these new cellular imaging technologies have the potential to dramatically improve the prevention, detection and therapy of epithelial cancers. In vivo confocal microscopy is a new technology that can provide detailed images of tissue architecture and cellular morphology in living tissue near real time. Pilot clinical trials show that confocal images of epithelial tissues can diagnose dysplasia with unprecedented specificity and sensitivity. Furthermore, flexible fiber optic instrumentation that permits high resolution in vivo imaging has been developed. In this renewal, a series of collaborative, integrated clinical and engineering studies are proposed to explore the clinical role of in vivo confocal imaging in the detection, management and therapy of caners of the oral cavity and to develop cost-effective approaches to provide clinical instrumentation for multi-center trials. The aims of this proposal are to: 1) Conduct a large prospective trial to estimate the sensitivity and specificity of reflectance based confocal imaging for detection of dysplasia in the oral cavity; 2) conduct a clinical trial to evaluate the role of in vivo reflectance confocal imaging to maximize surgical efficacy and minimize surgical morbidity by assisting in margin detection for tumor resection in the oral cavity; 3) conduct a clinical trial to examine the ability of in vivo reflectance confocal imaging to monitor response to induction chemotherapy in a group of young patients with cancer of the tongue; 4) assess the ability of in vivo reflectance confocal microscopy to provide a tool to monitor the field at risk without the need for biopsy, providing a powerful new intermediate endpoint marker to aid in chemoprevention studies. Finally, the miniaturized objectives designed in our previous work enable in vivo imaging but are expensive to manufacture and difficult to assemble. The fifth aim of this proposal is to design and construct inexpensive, injection-modeled optical elements that can be easily integrated with the inexpensive fiber optic imaging bundles used in current prototypes.